Circulating Micro-RNAs as Diagnostic Biomarkers for Endometriosis: Privation and Promise

Warren B Nothnick, Nothnick WB, Ayman Al‐Hendy, Al-Hendy A, Ayman Al-Hendy, Lue JR, John R Lue, John Lue
Journal of minimally invasive gynecology · 2015 · vol. 22(5) , pp. 719–726 · doi:10.1016/j.jmig.2015.02.021 · PMID:25757811 · PMC4489990 · W2081162415
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This paper discusses the potential of circulating microRNAs as stable, less invasive diagnostic biomarkers for endometriosis, contrasting them with current diagnostic limitations.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-19 · read from full text ⓘ

This paper reviews the rationale and background for using circulating microRNAs (miRNAs) as potential diagnostic biomarkers for endometriosis, contrasting them with current diagnostic approaches that rely on invasive laparoscopy and with earlier biomarker efforts such as CA125 that suffer from poor sensitivity and specificity. It outlines endometriosis epidemiology and the diagnostic problem of nonspecific symptoms and delayed, operator-dependent diagnosis, then describes miRNA biology and the proposed mechanisms by which circulating, RNase-resistant miRNAs may be released from disease tissues and detected in serum or plasma. The paper’s key premise is that endometriosis lesion–specific miRNAs, potentially assessed individually or as panels, could improve diagnostic accuracy compared with non-specific markers, while also acknowledging a major limitation in the field: achieving true disease specificity and clinically acceptable sensitivity/specificity is difficult. This paper is centrally about endometriosis—specifically the promise of circulating microRNAs as diagnostic biomarkers for endometriosis.

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Abstract

Endometriosis represents a major medical concern in women of reproductive age. One of the remaining major hurdles for successful treatment of endometriosis is the limitation of the process of timely disease diagnosis. A simple blood test for endometriosis-specific biomarkers would offer a more timely accurate diagnosis for the disease, thus allowing for earlier treatment intervention. Although there have been considerable efforts to identify such biomarkers, no clear choice for such noninvasive diagnostic tools has been identified. Micro-RNAs are small noncoding RNAs that have been evaluated intensively as biomarkers for several diseases, and they may hold promise for a diagnosis of endometriosis. In this review, we highlight the need for noninvasive testing for endometriosis, discuss the potential use of micro-RNAs as diagnostic tools for this disease, and consider potential limitations in the use of these small RNA molecules as diagnostic markers for endometriosis.
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The

Diagnostic markers are biological parameters that aid in the diagnosis of an existing disease, thus they should be specific to that disease and not show lack of specificity. Sensitivity, which is also referred to as the true positive rate, measures the proportion of actual positives which are correctly identified as positive for presence of a disease/condition. Specificity, which is also referred to as the true negative rate, measures the proportion of negatives which are correctly identified as negative for the presence of a disease/condition. Ideally, a perfect diagnostic biomarker would exhibit 100% sensitivity and 100% specificity. However, in the real world, this is rarely the case and acceptable levels of trade-off between sensitivity and specificity must be reached. The issue of sensitivity and specificity has been perhaps the major limiting factor in identifying an “endometriosis diagnostic marker.” Cancer antigen 125 (CA125) was one of, if not, the first biomarker evaluated for diagnosis of endometriosis ( 12 – 14 ), but this was not without question ( 13 ). First described as a biomarker for epithelial ovarian cancer ( 15 ), CA125 levels may still be considered when aiding in assessment of endometriosis severity ( 16 ), but this marker is clearly not specific for the disease. Like most putative endometriosis diagnostic biomarkers, CA125 suffers from poor sensitivity and specificity as elevated levels are detected in other gynecological pathologies ( 17 ), pregnancy ( 18 ) and pelvic inflammatory disorders ( 19 ). More recent emphasis has focused on the identification of panels of biomarkers for endometriosis diagnosis which, when assessed in combination, offer superior specificity and sensitivity compared to assessment of these markers singularly ( 20 , 21 ). Using this approach, the issues of specificity and sensitivity have been greatly improved over utilization of single markers such as CA125. While the approach of using panels of inflammatory and non-inflammatory markers ( 20 , 21 ) appear to hold great promise many of these markers are not specific to the endometriotic lesions themselves. MicroRNAs (miRNAs) have emerged as potential diagnostic markers for endometriosis based upon the premise of indentification of endometriosis-specific miRNAs, following suit to the field of cancer diagnostic biomarkers. Much of the initial work on miRNAs as diagnostic markers come from the field of cancer biology as several reports in the literature have identified oncomiRs or miRNAs which are specific to tumor tissue. Thus, the potential of endometriotic lesion specific miRNAs would in theory provide greater specificity and sensitivity compared to current biomarkers or panels of biomarkers. In the following pages, we provide background on miRNAs, their profiles in endometriotic tissue and our current understanding if these small RNAs can be used as diagnostic and/or prognostic markers for endometriosis.

Intro

Endometriosis is a chronic, recurrent disease in women of reproductive age. Endometriosis can present in patients with symptomatology such as cyclic pelvic pain, dysmenorrhea, dyspareunia or dyskinesia, and symptoms that are nonspecific and do not correlate with the extent or severity of the physical disease. It is estimated that up to 20 percent of women with endometriosis have concurrent chronic pelvic conditions including irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, fibromyalgia, and migraines ( 1 ). Endometriosis has been estimated to be the third leading cause of gynecologic hospitalizations in the United States ( 2 ). In current practice, the disease can only be diagnosed by invasive procedures which themselves are associated with morbidities and limitations. A simple blood test would offer multiple benefits over the current diagnostic approach, but to date, no “endometriosis-specific” biomarkers have been identified. MicroRNAs (miRNAs) are small non-coding RNA molecules which possess superior stability in biological fluids and offer multiple benefits as potential diagnostic markers compared to current peptide/protein based tests in general. The potential utility of miRNAs as diagnostic markers for non-gynecological diseases as well as cancer has recently gained considerable attention.

Microrna

miRNAs are a class of small non-coding regulatory RNAs that regulate gene expression post-transcriptionally impacting subsequent translation of protein ( 22 , 23 ). miRNAs are vital for normal development and function of essentially all organs and alterations in their normal pattern of expression have been associated with numerous diseases of these organ systems. Genes for specific miRNAs are primarily intergenic, residing between genes, and intronic, residing within introns. Less common are miRNA genes which have been shown to makeup entire introns as well as reside within exons ( 24 , 25 ). miRNA transcription is mediated by polymerase II (or III) as the initial long primary RNA transcript (pri-miRNA) is capped (MGpppG) and polyadenylated ( 26 ). Beginning in the nucleus, miRNA transcription begins with transcription of the pri-miRNA transcript which then binds with the RNA-binding protein DGCR8 (DiGeorge syndrome critical region 8). The pri-miRNA-DCGR8 complex is then cleaved by Drosha (an RNAse III enzyme). This cleavage yields a stem-loop precursor miRNA (pre-miRNA). An alternative pathway has also been described by which pre-miRNA hairpins can be generated by the lariat debranching enzyme, Ldbr, in the Drosha-independent mitron pathway ( 27 , 28 ). Regardless of pathway, upon liberation, pre-miRNAs are then exported from the nucleus via exportin 5 and RAN-GTP into the cytoplasm. Once in the cytoplasm, a second RNAse III enzyme, Dicer, cleaves the pre-miRNA into a transient RNA duplex which results in the generation of two strands. One of the two strands (deactivated strand) accumulates in P-bodies where they are either stored or degraded ( 29 ). The remaining strand (guide strand which is the mature miRNA) is preferentially loaded onto the RNA-induced silencing complex (RISC) which is composed of Dicer, a TAR RNA-binding protein (referred to as TRBP) and one of four different Argonaute (Argo) proteins ( 30 ). Once within the RISC, miRNAs bind to the 3′untranslated region (or UTR) of the target mRNA transcript. If the binding of the miRNA to the 3′UTR “seed sequence” exhibits perfect base pairing, the mRNA transcript is degraded and mRNA translation does not occur ( 31 ). If base pair binding homology between miRNA and 3′ UTR of the mRNA is imperfect, mRNA translation is inhibited. While the majority of the literature supports the notion that miRNAs inhibit translation, there is some evidence that miRNAs can actually enhance translation through alterations in the Argo component of the RISC ( 23 ). Thus, while miRNAs appear to primarily regulate translation in an inhibitory fashion, they also may enhance translation in certain biological scenarios. In addition to modulating protein expression within the same cell from which they are transcribed, miRNAs have also been proposed to elicit functions in distal cells/organs via transport through the circulation. Circulating miRNAs exist in cell free form and are thought to be protected from endogenous RNA activity by complexing with lipoproteins and/or residing in microvessicles, exosomes, and microparticles ( Figure 1 ). Recipient cells may then take-up circulating miRNAs through endocytosis and/or by binding with cell surface receptors which recognize the miRNA-binding proteins to which the miRNAs are complexed. Once taken into the cell, miRNAs can elicit similar biological responses as miRNAs which are retained in the originating host cell. The observation that miRNAs are released by cells into the circulation has led to an intense effort in identifying disease-specific miRNAs which may be used as diagnostic markers for the disease. This has been evident in the study of many diseases with cancer being the most obvious. The simple premise that carcinoma cells release specific miRNAs into the circulation which can be used as diagnostic markers for the presence of these cancerous cells has led to intense investigation and great promise for miRNAs as potential diagnostic markers for disease. In the following paragraphs, we discuss our current knowledge on endometriotic lesion-derived miRNAs, their detection in serum and/or plasma and their potential promise as diagnostic markers for endometriosis.

Micrornas

The study by Suryawanshi and colleagues ( 42 ) raises an important issue on specificity of miRNAs and endometriosis. For this discussion, we will focus on miR-199a and miR-122 as their expression has been reported to be elevated in the circulation of women with endometriosis but yet neither of these miRNAs has been reported to be significantly over-expressed by endometriotic lesions. Thus, the first question that may be raised is that if these miRNAs are not derived from the lesions themselves, what are the sources of these miRNAs and the mechanisms which generate their elevated levels? Elevated circulating levels of both miR-199a and miR-122 have been reported for other, non-gynecologic diseases. Circulating levels of miR-199a are elevated in subjects with inflammatory bowel disease (IBD; 53), type 2 diabetes ( 54 ), and hepatocellular carcinoma ( 55 ) among other diseases. miR-122 is has been demonstrated to be elevated in the circulation of subjects with liver disease ( 56 , 57 ), gastric cancer ( 58 ) and cardiovascular disease ( 59 ). While symptoms for these diseases differ from those of endometriosis and would undoubtedly assist in differential diagnosis, the goal for any diagnostic marker would be early detection, ideally before the manifestation of the more severe symptoms associated with the disease being diagnosed. Potential confounding factors could include the presence of inflammatory conditions which are associated with many diseases including IBD and cancer among others. A second area which needs careful evaluation is the determination of the most optimal way to quantitate serum miRNAs as diagnostic markers and the potential need for an internal normalizing factor. The studies discussed in this review all report the levels of expression of the defined miRNAs as fold changes from controls. As these controls vary greatly from study to study, so does the reported fold change in miRNA expression. A more quantitative index will need to be established and this will require new technology as well as larger, more diverse sample sizes. Digital PCR (dPCR) is a technology that may allow for more precise quantitation of miRNAs concentrations in serum/plasma ( 60 ). Unlike qRT-PCR, dPCR is not dependent on the number of amplification cycles to determine the initial sample amount, thereby eliminating the reliance on uncertain exponential data to quantify target miRNAs (or nucleic acids in general) and therefore provides absolute quantification of the amount of target. dPCR coupled with larger sample sizes may allow for the development of normal ranges for given miRNAs in biological fluids from women without endometriosis. This “normal” range could then be used as a standard, much like blood glucose, cholesterol and the likes, to establish what are the normal and abnormal levels of a given miRNA to help distinguish or diagnosis those women with versus those without endometriosis. miRNA values are often normalized to an endogenous “control” miRNA in biological samples to control for variation among samples in processing. There still remains great debate in how best to normalize miRNA values in tissue/cells and these as well as other concerns are also inherent when assessing circulating miRNA levels ( 61 ). Currently, U6 and miR-16 are the most common endogenous controls in the research of miRNAs in tissues and cells, both of which come under criticism as internal references for assessing biological fluid miRNA levels as U6 lacks stability and levels of expression are influenced by sample processing and storage, while miR-16 levels have been shown to be altered in states of inflammation ( 40 ), stress ( 62 ) and in subjects with hepatocellular carcinoma ( 63 ). These results question the use of U6 and miR-16 as internal reference miRNAs suitable for normalization of test miRNA values. An additional area which will need to be standardized is the processing and handling of biological fluid specimens. Differences in experimental approaches undoubtedly may introduce differences among study results. How blood samples are obtained and processed as well as how the RNA is extracted and amplified will need to be standardized. These not only hold true for potential limitation for miRNA quantitation but also the application of dPCR for these assessments.

Conclusions

In summary, endometriosis represents a major medical concern in women of reproductive age. One of the major hurdles in successful treatment of endometriosis that remains is the limitation in the process of timely disease diagnosis. MiRNAs represent potential biomarkers for early detection of the disease. miRNAs in general are more stable in circulation compared to most proteins and peptides; a characteristic that would reduce sample processing artifacts. Further, the potential for identification of endometriotic lesion-specific or enriched miRNAs as biomarkers would offer increased specificity and sensitivity compared to currently used or proposed biomarkers. While to date, endometriotic lesion-specific miRNAs have not been identified, the possibility still exists of identifying miRNAs (or a panel of miRNAs) whose expression may be altered in response to the presence of the disease. For this to occur and to achieve the goal of non-invasive diagnostic markers for the disease, larger studies must be conducted enrolling a diverse patient population to minimize overlap with other diseases and/or conditions. This will provide a range of normal miRNA values which can provide ranges to distinguish disease from non-disease. Further, assessment of circulating miRNA will require uniformity in specimen collection and processing to avoid the potential of false negatives or positives. Taking these factors into account will provide the best approach in identifying endometriotic lesion-specific or enriched miRNAs which may prove to be the ever-elusive diagnostic biomarker for this enigmatic disease.

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endometriosis

MeSH descriptors

Endometriosis MicroRNAs Biomarkers Biomarkers Endometriosis Endometriosis Female Gene Expression Profiling Humans Intercellular Signaling Peptides and Proteins MicroRNAs Sensitivity and Specificity

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